Elucidating neural molecular mechanisms underlying metabolic disorders-induced neuropsychiatric disorders in mice on prolonged high fructose diet.

Metabolic disorders (MetDs), driven mostly by lifestyle changes are growing at an alarming rate, and have cardiovascular and cerebrovascular consequences, eventually leading to various neuropsychiatric disorders. Considering a dearth of studies, we modeled MetDs-like conditions in C57BL/6 Ncrl mice on prolonged 60% high fructose diet (Hfr) for 56 weeks. The metabolic assessments revealed significant changes in various MetDs-related physiological and biochemical parameters in the Hfr group compared to the control (Ctrl) group such as reduced lean mass, hyperlipidemia, elevated liver function markers (SGPT, SGOT), and kidney function markers (creatinine, alkaline phosphatase). However, hyperglycemia and glucose intolerance were not observed. Interestingly, the prolonged Hfr diet accelerated the onset of aging. But just 10 days of chronic unpredictable mild stress (CUMS) resulted in mild insulin intolerance as shown by the oral glucose tolerance test (OGTT). Further, these animals developed neuropsychiatric disorders-like phenotype. Transcriptomic analysis of the prefrontal cortex (PFC) region led to uncovering of hundreds of differentially expressed genes (DEGs) between the groups, including the known markers: pro-inflammatory cytokines (IL1B, IL6, TNFα) chemokines (CXCl10,12, CCL4,8), innate immune regulators (TLR4), neuroinflammatory regulators (NLRP3,4), neurotrophic and angiogenic factor (VEGF), thus correlating with MetD-induced neuropsychiatric (cognitive and affective) disorders. The pathway analysis of the DEGs highlighted perturbations of various signaling pathways already implicated in neuropsychiatric disorders. Furthermore, dysregulation of a few key epigenetic regulators including the critical metabolic sensor SIRT6 and its neuroinflammatory and immune target genes, supports our hypothesis that epigenetic dysregulation underlies lifestyle changes (high-calorie diet and chronic stress)-induced susceptibility to diseases.